Over recent years, there has been an increasing interest, in general and in particular within the pharmaceutical industry, to provide products of a larger variety as regards the composition and release profile of the ingredients. In order to produce tablets from for instance active pharmaceutical ingredients (API) and various excipients, the product streams are normally supplied in a powdery form to a tablet press, such as for instance the rotary tablet press described in WO 03/020499 A1 (Courtoy).
One of the later developments of tablets includes the so-called multiple unit tablets. A specific example within this group of tablets is the Multiple-Unit Pellet System tablets, commonly referred to as MUPS®, a registered trademark by AstraZeneca. In multiple unit tablets, the active ingredients are homogeneously distributed in subunits, which can be granules, pellets or even microtablets. By applying specific coatings around the subunits, the release profile of the active ingredient can be controlled or modified. Before the subunits can be compressed into tablets, they are blended with one or more excipients (e.g. fillers, binders, disintegrants etc.). The excipients are required to obtain tablet with desired hardness, friability and disintegration characteristics and fulfil a cushioning role to prevent damage of the pellets during compression.
The production of multiple unit tablets is generally recognized as complicated and challenging. This is in part due to the number of steps involved in the process, viz. pellet manufacture and coating, and the subsequent mixing and blending with excipients, followed by tabletting and coating or other after-treatment of the finished tablets. Furthermore, it is important to ensure that the pellets are not damaged during compression. One other major challenge resides in the fact that during production, the multiple unit tablet feed is particularly prone to segregation due to the broad particle size distribution and/or the significant difference in particle size between the subunits and the excipient(s), respectively. The theory underlying the possible mechanisms of segregation, including percolation and elutriation, is relatively complicated but it is generally recognized that difference in particle size and particle size distribution of the materials involved have a great impact. The average particle size of the pellets typically lies in the range 200-2000 μm, whereas the particle size of the excipient typically lies in the range 100-200 μm. In turn, this entails that during handling and transport from the blender and the intermediate hopper towards the tablet press, there is a risk of segregation of the feed, which is detrimental to the distribution within the feed and which may also entail damage of the pellets due to pellet-to-pellet contact. In addition, the segregation may have a large impact on the content uniformity of the tablets and there is a risk of producing tablets of an inferior quality or at least outside specification if not attended to.
A further issue in the overall production costs is the configuration of the process line. Typically, manufacturing processes hitherto employed within the pharmaceutical field are most often of a batch nature. As an example, WO 02/067854 A2 (King Pharmaceuticals) may be cited. Here, an apparatus for transporting drug formulations from a blender to a tabletting machine is disclosed, wherein a mass flow of material in multiple stages via a portable container is aimed at. Batch manufacturing processes have a number of advantages and provide satisfactory results within many areas. However, due the increasingly widespread application of regulated criteria for monitoring and controlling in particular pharmaceutical manufacturing processes, and to the general increase in the demands to quality by design, the level of quality of monitoring and control attainable by a batch process is often not sufficient, i.a. due to the fact that settings are fixed. Furthermore, a relatively large buffer volume is required, entailing undesired back-mixing of the material stream. As a consequence, manufacturers' and customers' focus of interest has shifted to continuous processes.
In WO 2010/128359 A1 (GEA Pharma Systems), a contained module being able to operate by a fully continuous process for the production of tablets is devised. In such modules and processes, one or more mixing and transportation units are utilised. The term “mixing unit” should in this context be understood in its broadest terms. Thus, the mixing unit refers to a unit operation generally capable of mixing or otherwise processing one, two or more components into a desired form. The mixing unit may thus also be capable of modifying the physical form of dry component(s) processed in the mixing unit, e.g. a feed stream of powder(s) may be converted to a granulate comprising the component(s). The mixing unit may be a granulator for making a granulate from dry powders, such as a granulator to which a granulating liquid is added, or a roller compactor. Further examples include a twin screw blender and a twin screw granulator. Furthermore, the mixing unit may include such equipment as a dryer, a dry blender, a continuous dry blender or the like.
The contained module and the method disclosed in the abovementioned document WO 2010/128359 A1 have proven to function very well with APIs and excipients in powdery form and with a relatively homogenous particle size and particle size distribution, and are particularly efficient in providing improved protection of the operator and the environment by the containment feature. In practical embodiments, the module comprises a number of mixing units in the process line.
However, with respect to the processing/tabletting of at least two product streams having significantly different particle sizes and/or particle size distributions, there is still room for improvement. This applies in particular to tabletting of pharmaceuticals, nutriceuticals, detergents, ceramics, metallic powders and nuclear fuels.